To initiate pharmacological studies of benzodiazepine physical dependence, an animal model of this neuropathic state has been developed. Based on the "chronically equivalent" dosing principle (Boisse and Okamoto, J.P.E.T. 204:497-540, 1978), a rat model of chlordiazepoxide dependence culminating in a severe withdrawal has been developed. Because peak drug effect is steady throughout treatment, tolerance and its functional and dispositional components will be assessed from the rise in dose and blood concentration and concentration decline in blood over time. Blood levels of chlordiazepoxide and its active metabolites will be determined by a high pressure liquid chromatographic micro-method developed for this purpose. Chlordiazepoxide withdrawal will be quantitatively characterized to serve as a standard for comparative studies of dependence, cross-dependence and withdrawal suppression. A phenobarbital dosing regimen "chronically equivalent" to chlordiazepoxide has been developed to permit the comparative evaluation of tolerance and dependence between barbiturate and benzodiazepine classes. By pharmacokinetic monitoring during withdrawal and cross substitution of drugs before withdrawal, pharmacokinetic differences should be removed to ultimately compare relative physical dependence capability. The rat model of chlordiazepoxide dependence will provide a necessary pharmacologic reference to explore electrophysiological correlates of synaptic alteration during withdrawal. The segmental spinal reflexes of the lumbar cord will be tested for specific alterations in excitatory and inhibitory synaptic processes.